ABSTRACT The fundamental gap existing in understanding the origins of Chronic Obstructive Pulmonary Disease (COPD) is centrally responsible for the lack of any disease-modifying therapies for this highly prevalent and lethal disease. Developing and testing such therapies will require defining the biologic process occurring in the human lung that induce small airway abnormality (SAA), the earliest COPD pathology, and which cause transition from potentially reversible SAA to irreversible emphysema or airway remodeling. Our long term goal is to arrest COPD progression by understanding its earliest stages. Our Central Hypotheses are: SAA (detectable by chest imaging) identifies susceptible younger smokers at heightened risk of anatomic disease progression. SAA results, in part, from distinctive types of auto-aggressive host immune reactions (detectable by measuring epithelial gene signatures and immune cell function) and from altered airway surface liquid (detectable by analyzing airway mucin). These processes collectively lead to SAA detectable by a novel high- resolution chest computed tomography (HRCT) metric (PRMfSAD) we have developed. The knowledge gained in this project will allow us to identify individuals with disease progression noninvasively, while also defining pathophysiological mechanism(s) that can be therapeutically targeted. In this project we will leverage the infrastructure of SPIROMICS, an NHLBI funded COPD program, to recruit a new cohort of individuals aged 35- 50 years, a group which are not represented in the current cohort. Subjects will be analyzed at clinical visits at enrollment and after three years of follow-up. At each visit, they will undergo clinical data collection, post- bronchodilator spirometry, HRCT, induced sputum, and exhaled breath condensate. One hundred subjects will also undergo a single research bronchoscopy. In Aim 1, we will determine the relationship between HRCT- defined SAA and disease progression in early COPD. Specifically we will define the relationship between baseline PRMfSAD and development of radiographic disease progression to PRM defined emphysema over three years. In Aim 2 we will explore the biological basis of SAA in early COPD by analysis of lung-derived biomarkers. To achieve this we will collect biospecimens by bronchoalveolar lavage (BAL), and from segmental & distal airways. We will correlate baseline PRMfSAD with an IL-17 gene signatures in airway epithelium. Secondary analyses will explore correlations of baseline PRMfSAD with the activation states and functional capacity of BAL leukocytes, as well as with total airway mucin concentration. In Aim 3 we will determine whether sputum can serve as a non-invasive biomarker of early COPD. Specifically we will: a) correlate baseline sputum total mucin concentration with baseline SAA; and, (b) correlate baseline sputum total mucin concentration and its change over 3 years with progression of HRCT abnormalities. This approach enables us to link HRCT and pathologic abnormality to define potentially targetable mechanisms laying the foundation for developing disease-modifying therapies.